The compound (-)-trans-4-((4'-fluorophenyl)3-(3'4'-methylenedioxyphenoxymethyl)-piperid ine, commonly known as paroxetine, is a viscous oil and poorly water soluble drug with a commercial need for useful pharmaceutical compositions. A solid dispersion of paroxetine or its acid addition salt, never described before now in the literature, would provide a solid product on a commercial scale with good handling qualities and physiological acceptability without the need or expense to manufacture crystalline materials.
Pharmaceutical compositions with good dissolution and bioavailability can be formulated from solid dispersions of pharmaceutically active ingredients. Advantages claimed for pharmaceutical solid dispersions include potential use in controlled release formulations, stabilizing the drug from polymorphic conversions, improving poor handling properties of drug substances and protecting certain drugs against decomposition during administration. Solid dispersions of pharmaceutically active ingredients can be formed from a number of pharmaceutically acceptable carriers. U.S. Pat. No. 4,933,360 describes a novel process and product comprising chlorthalidone as the pharmaceutical active ingredient and polyvinylpyrrolidone (PVP) as the pharmaceutically acceptable carrier. The techniques have been described in general by W. L. Chiou et al., J. Pharm. Sci. 60(28)(1971) and S. Riegelman et al, U.S. Pat. No. 4,151,273. As defined in the Chiou article the term "solid state dispersion" means a dispersion of one or more active ingredients in an inert carrier or matrix in a solid state prepared by a melting (fusion), solvent, or combined melt-solvent method. The dispersion of an active ingredient in a solid carrier or diluent by traditional mechanical mixing is not included within the definition of this term.
In the "solvent method", the active ingredient is conventionally dispersed in a water soluble carrier by dissolving a physical mixture containing the active ingredient and the pharmaceutically acceptable carrier in a common organic solvent and then removing the solvent by evaporation. The resulting solid dispersion is recovered and used in the preparation of suitable pharmaceutical compositions formulated using conventional methods.
Manufacture of solid dispersions by the fusion or "melt" process involves combination of the pharmaceutically acceptable carrier and the poorly water soluble drug where the two components are allowed to melt at temperatures at or above the melting point of both the drug and the carrier. In the fusion process, the drug and carrier are first physically mixed and then both are melted. The molten mixture is then cooled rapidly to provide a congealed mass which is subsequently milled to produce a powder. Spray-congealing techniques used to produce pellets have been described by Kanig (J. Pharm. Sci. 53, 188 (1964)) for dispersions containing mannitol and by Kreuschner et al. (Acta Pharm. Tech. 26, 159 (1980)) for phenylbutazone-urea.
In general, problems which can be associated with known melting (fusion), solvent, melt solvent, and coprecipitation techniques can include excess solvent usage, identifying carrier/drug combinations that can be conveniently melted (fused) or codissolved, the use of heat to effect solution or fusion which may result in decomposition of the drug and/or carrier, and identifying conditions and properties effecting coprecipitation. Salts of drugs may present particular problems with identifying organic solvents or solvents capable of dissolving both the drug and a pharmaceutically acceptable carrier.
U.S. Pat. No. 4,007,196 discloses paroxetine as an inhibitor of 5-hydroxytryptamine (5HT) uptake and thus of therapeutic use as an anti-depressant. Paroxetine is well known and widely marketed as a medicinal agent. As disclosed in U.S. Pat. No. 4,007,196, paroxetine is obtained as the free base and then converted to its maleate salt. However, paroxetine is a poorly water soluble drug and difficult to formulate into useful pharmaceutical compositions.
U.S. Pat. No. 4,721,723 indicates that because of its basicity, it is preferred that paroxetine be used as a therapeutic agent in the form of an acid addition salt. The free base is a viscous oil which is difficult to handle and formulate into a finished dosage form for therapeutic use. As such, U.S. Pat. No. 4,721,723 further discloses crystalline paroxetine hydrochloride hemihydrate as a novel material with better handling properties than anhydrous paroxetine hydrochloride which is an hygroscopic solid with poor handling properties.
In general, the hydrochloride salt of a basic compound is preferred for therapeutic use because of its physiological acceptability. Additionally, a pharmaceutically active ingredient should not contain appreciable amounts of bound or unbound organic solvent. Once the salt has been formed, it must be isolated from solvents by filtration or other means in order for the paroxetine salt to be conveniently formulated into a pharmaceutical composition. Many solvents, including water, form solvates or clathrates of paroxetine hydrochloride wherein the solvent cannot be removed by conventional drying techniques such as vacuum oven drying. U.S. Pat. No. 4,721,723 discloses the hemihydrate solvate form of paroxetine hydrochloride while International Publication Number WO 96/24595 discloses paroxetine hydrochloride solvates other than the propan-2-ol solvate as precursors in the preparation of paroxetine hydrochloride substantially free of bound organic solvent. Additionally, International Publication Number WO 96/24595 also discloses four novel paroxetine hydrochloride anhydrates substantially free of bound solvent. However, none of the above publications specifically describe the stability or hygroscopicity of noncrystalline anhydrates of paroxetine hydrochloride in a solid dispersion.
The present invention relates to novel processes for incorporating paroxetine, a poorly water soluble drug, into a solid dispersion and its use in pharmaceutical compositions containing the same.
It has now been surprisingly found that solid dispersions of anhydrous paroxetine hydrochloride can be manufactured by a fusion process using the free base of paroxetine, and dry hydrogen chloride gas at temperatures substantially lower then the melting point of paroxetine hydrochloride using a pharmaceutically acceptable carrier with a melting point significantly lower than that of anhydrous paroxetine hydrochloride. The resulting solid dispersion is substantially free of organic solvent, is anhydrous and has improved handling properties.
Furthermore, it has been found that solid dispersions of anhydrous paroxetine salts, preferably the hydrochloric acid salt, can be manufactured by a novel solvent process using a pharmaceutically acceptable carrier, paroxetine free base, a non-aqueous solvent and a solution or gas of the acid addition salt.
The manufacturing of noncrystalline anhydrates of paroxetine hydrochloride in a solid dispersion improves the formulating of paroxetine free base, provides a solid which is readily formulated into a commercial dosage form, eliminates the additional steps to manufacture crystalline material for handling purposes and presumptively reduces manufacturing costs associated with those steps.